1. Field of the Invention
The present invention relates to new compounds and pharmaceutical compositions comprising them, which have inhibition effects on osteoclast differentiation. The pharmaceutical composition comprising new compounds according to the present invention can be used as medicines for treating metabolic bone diseases such as bone metastatic cancer, solid cancer bone metastasis, musculoskeletal complication by solid cancer bone metastasis, hypercalcemia by malignant tumor, multiple myeloma, primary bone tumor, osteoporosis, rheumatoid arthritis, osteoarthritis, periodontal disease, inflammatory resorption of alveolar bone, inflammatory resorption of bone and Paget's disease.
2. Description of the Related Art
Breast cancer is one of the cancers known as the most studies have made compared to all the other cancers. While the studies researched that the breast cancer can be caused by environmental and genetic factors, a certain cause of the cancer has not yet been identified. However, various study results showed possible certain causes of the cancer and there is no controversy that the female hormone estrogen plays an important role in the carcinogenesis of breast cancer. Since breast cells proliferate and differentiate by estrogen stimulations, the risk of breast cancer may be determined by the estrogen exposure period. It means that an increased incidence of breast cancer depends on a longer exposure period to estrogen. In addition, excess intakes of nutrients and fat, genetic factors, obesity, and a hormonal imbalance caused by a long-term administration of contraceptive and female hormone therapy have also been suggested as a possible cause of breast cancer.
The metastasis of cancer often leads to death in cancer patients, especially the breast cancer is recurred by a bone metastasis. According to the clinical cases, it has been reported that the metastasis into the bone tissues was occurred in the 30%-40% of patients who have an early stage transition and in more than 90% of patients who died from the transition. Roughly three causes are considered to induce the bone metastasis. First, a high blood stream mobility following to a lot of blood flow around the red bone marrow of breast cancer cells causes to high access of breast cancer cells to bone tissues. Second, the revelation of surface molecules of orphan cancer cell, i.e., homing receptor of breast cancer cell, and absorbance molecule of bone tissue matrix cells, i.e., drawing ligand molecule may cause it. Finally, existing calcium (Ca2+) and growth factor within the bone tissues promote a proliferation of breast cancer cells. When the bone metastasis occurred by a single or a few of breast cancer cells, bone destruction (i.e., bone resorption) may be induced, and the above factors released through the above processes stimulate the proliferation of breast cancer (i.e., vicious cycle) and the majority of patients eventually leads to death.
The bone resorption proceeds by the actions of osteoclasts. The differentiation of osteoclasts may be initiated by the revelation of PTHrP (paratyroid hormone-related protein) and GM-CSF (granulocyte macrophage colony-stimulating factor) molecules which were occurred by the regulated transcription action of activated NF-kappa B (Nuclear Factor-kappa B) in the breast cancer. The PTHrP increases RANKL (RANK ligand) which competes with OPG (osteoprotegrin) in the RANK (receptor activator of NF-kappa B), and concurrently decreases the revelation of OPG (i.e., RANKL antagonist or RANK inhibitor), and thus the PTHrP facilitates the binding of RANK and RANKL. When the RANKL binds to the RANK, the revelation of osteoclast precursors increase. The GM-CSF helps to the generation and differentiation of osteoclast precursors and differentiation of osteoclasts. The NF-kappa B is one of proteins which involved in the cell survival, regulation of immune response, cancer or inflammation, and it has different functions depending on the types of interacting cells and acting point of interaction, like many other transcription factors. NF-kappa B always exists as an active form in the breast cancer cells, and regulates the mechanism of carcinogenesis, proliferation, and metastasis. The activation of NF-kappa B is regulated by IKK (IkB kinase) which phosphorylates IKB (Inhibitor-kB), the activated NF-kappa B is translocated into the nucleus and transcription of target gene initiated.
The only commercially used-medicine for bone disease (bone metastasis of breast cancer and osteoporosis) is zoledronic acid of Novartis. The zoledronic acid is one of bisphosphonates, transformed form of pyrophosphate which used to prevent corrosion of metal pipes etc.
Pharmacokinetically, pyrophosphates having P—O—P can be easily hydrolyzed however, bisphosphonates having P—C—P cannot be easily hydrolyzed and thus it has relatively long-term half-life. Bisphosphonates is used as a treatment for osteoporosis since it reduces bone resorption by inhibiting osteoclasts. R1 among R1 and R2, two lateral chains, binding to carbon atom of bisphosphonates can be binded to calcium of bone by hydroxide (—OH) group, and R2 can be modified in the various forms to increase the inhibition effect of bone resorption. Most of the bisphosphonates are structurally highly hydrophilic and the absorption rate is very low and thus they are formulated to the intravenous injection dosage form. Bisphosphonates attach to the bone surface which the bone formation actively made, and inhibit the maturation of osteoclasts and prevent bone resorption. Also bisphosphonates inhibit the recruitment of osteoclasts to the region of bone resorption and reduce the generation of cytokines to stimulate the bone resorption. Bisphosphonates prevent the invasion of tumor cells and induce the apoptosis of tumor cells in the bone matrix.
Bisphosphonates may have many side effects, such as stroke and atrial fibrillation and the biggest rising problem is known as a bisphosphonates induced osteonecrosis of the jaws (BIONJ), and the exact mechanism of BIONJ is still unknown. BIONJ is a severe bone disease that affects the maxilla, the mandible and the tooth root and the definitive symptom is the exposure of mandibular or maxillary bone. In healthy bone tissue there is a homeostasis between bone resorption and bone apposition. Diseased or damaged bone is resorbed through the osteoclasts mediated process and then osteoblasts form new bone to replace it, thus maintaining healthy bone density. This process is commonly called remodeling.
The main pharmacological action of bisphosphonates is inhibition of the maturation of osteoclast driven bone resorption, and thus bone resorption is inhibited by bisphosphonates, it prevents bone formation by osteoblasts, bone generation is not occurred and thereby micro-damage and fractures are cumulated. Bisphosphonates may affect to the mucous membrane of the gingiva and the tooth root to be exposed outside of the gingiva. Especially in case of frequently masticated jaw bone, the bone turnover rate of jaw is about 10 times higher than the one of normal bone, and thus it is easily affected by bisphosphonates. Also, the bisphosphonates increases the possibility of occurrence of BIONJ by blocking a sufficient blood supply through the inhibition of blood vessels by bisphosphonates.